Virocomb E Combi Pack

Uses

Efavirenz in combination with other antiretroviral agents is used for the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV- RNA levels and CD4 cell counts in controlled studies of up to 24 weeks in duration. At present, there are no results from controlled trials evaluating long term suppression of HIVRNA with Efavirenz.

Lamivudine is used for the treatment of chronic hepatitis B associated with evidence of hepatitis B viral replication and active liver inflammation.

Zidovudine, a nucleoside reverse transcriptase inhibitor, is used for combination with other antiretroviral agents for the treatment of HIV-1 infection.Prevention Of Maternal-Fetal HIV-1 Transmission Zidovudine is used for the prevention of maternal-fetal HIV-1 transmission. The indication is based on a dosing regimen that included 3 components:

• Antepartum therapy of HIV-1–infected mothers
• Intrapartum therapy of HIV-1–infected mothers
• Post-partum therapy of HIV-1–exposed neonate

Points to consider prior to initiatingZidovudine in pregnant women for the prevention of maternal-fetal HIV-1 transmission include:

• In most cases,Zidovudine for prevention of maternal-fetal HIV-1 transmission should be given in combination with other antiretroviral drugs.
• Prevention of HIV-1 transmission in women who have receivedZidovudine for a prolonged period before pregnancy has not been evaluated.
• Because the fetus is most susceptible to the potential teratogenic effects of drugs during the first 10 weeks of gestation and the risks of therapy withZidovudine during that period are not fully known, women in the first trimester of pregnancy who do not require immediate initiation of antiretroviral therapy for their own health may consider delaying use; this indication is based on use after 14 weeks’ gestation.

Virocomb E Combi Pack is also used to associated treatment for these conditions: Human Immunodeficiency Virus Type 1 (HIV-1) InfectionHepatitis B Chronic Infection, Human Immunodeficiency Virus (HIV) InfectionsHIV Transmission, Human Immunodeficiency Virus (HIV) Infections, Perinatal HIV transmission

How Virocomb E Combi Pack works

Similar to zidovudine, efavirenz inhibits the activity of viral RNA-directed DNA polymerase (i.e., reverse transcriptase). Antiviral activity of efavirenz is dependent on intracellular conversion to the active triphosphorylated form. The rate of efavirenz phosphorylation varies, depending on cell type. It is believed that inhibition of reverse transcriptase interferes with the generation of DNA copies of viral RNA, which, in turn, are necessary for synthesis of new virions. Intracellular enzymes subsequently eliminate the HIV particle that previously had been uncoated, and left unprotected, during entry into the host cell. Thus, reverse transcriptase inhibitors are virustatic and do not eliminate HIV from the body. Even though human DNA polymerase is less susceptible to the pharmacologic effects of triphosphorylated efavirenz, this action may nevertheless account for some of the drug's toxicity.

Lamivudine is a synthetic nucleoside analogue and is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). This nucleoside analogue is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain termination.

Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. It competes with the natural substrate dGTP and incorporates itself into viral DNA. It is also a weak inhibitor of cellular DNA polymerase α and γ.

Dosage

Virocomb E Combi Pack dosage

It is recommended that Efavirenz be taken on an empty stomach, preferably at bedtime.

Adults: The recommended dosage of Efavirenz is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs).

Pediatric Patients: Following table describes the recommended dose of Efavirenz for pediatric patients 3 years of age or older and weighing between 10 and 40 kg. The recommended dosage of Efavirenz for pediatric patients weighing greater than 40 kg is 600 mg, once daily.

10 to <15 kg: 200 mg

15 to < 20 kg:250 mg

20 to < 25 kg: 300 mg

25 to < 32.5 kg:350 mg

32.5 to < 40 kg: 400 mg

40 kg: 600 mg

The recommended oral dose of Lamivudine for the treatment of chronic hepatitis B in adults is 100 mg once daily.

Prophylaxis of HIV infection in neonates:

• Child:2 mg/kg 6 hrly, starting within 12 hr after birth and continuing for 6 wk.

HIV infection:

• Adult:250 mg or 300 mg bid, in combination with other antiretroviral agents.
• Child:As soln: 4 to <9 kg: 12 mg/kg bid; 9 to <30 kg: 9 mg/kg bid; ≥30 kg: 250 mg or 300 mg bid. As cap/tab: 8-13 kg: 100 mg bid; 14-21 kg: 100 mg in the morning, 200 mg in the evening; 22-30 kg: 200 mg bid; ≥30 kg: 250 mg or 300 mg bid. Alternatively (based on BSA), 480 mg/m2daily in 2-3 divided doses. Doses are given in combination with other antiretroviral agents.

Prophylaxis of maternal-fetal HIV transmission:

• Adult:100 mg 5 times daily, starting on the 14th wk of gestation until the start of labour.

May be taken with or without food.

Side Effects

Rashes, psychiatric or CNS disturbances, amnesia, agitation, confusion, dizziness, vertigo, headache, euphoria, insomnia or somnolence, impaired concentration, abnormal thinking or dreaming, depersonalisation, convulsions, hallucinations, nausea, vomiting, diarrhoea, pancreatitis, fatigue, hepatic failure, photoallergic dermatitis; autoimmune disorders (e.g. Graves’ disease, polymyositis, Guillain-Barre syndrome), osteonecrosis. Accumulation or redistribution of body fat (lipodystrophy) including central obesity, peripheral and facial wasting, buffalo hump, breast enlargement, cushingoid appearance. Metabolic abnormalities e.g. hypercholesterolaemia, hyperglycaemia, hypertriglyceridaemia, hyperlactataemia, insulin resistance.

Several serious adverse events reported with lamivudine (lactic acidosis and severe hepatomegaly with steatosis, post treatment exacerbations of hepatitis B, pancreatitis, and emergence of viral mutants associated with reduced drug susceptibility and diminished treatment response). Malaise, fatigue, fever, ENT infections, sore throat, nausea, vomiting, abdominal discomfort, pain, diarrhea, myalgia, arthralgia, headache, skin rashes may occur. Lactic acidosis and severe hepatomegaly with steatosis, have been reported.

Dizziness, headache, malaise, myalgia, GI symptoms (e.g. abdominal pain, diarrhoea, nausea, vomiting), anorexia, immune reconstitution syndrome, lipodystrophy, metabolic abnormalities, mitochondrial dysfunction, osteonecrosis; raised liver enzymes, creatine phosphokinase; hyperbilirubinaemia, myalgia, myositis. Rarely, aplastic anaemia, pure red cell aplasia, pancytopenia, thrombocytopenia, rhabdomyolysis, cardiomyopathy, convulsions, pancreatitis.

Toxicity

The most common reported adverse reactions (incidence ≥15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough.

Symptoms of overdose include fatigue, headache, nausea, and vomiting. LD₅₀ is 3084 mg/kg (orally in mice).

Precaution

Patient with history of seizures and psychiatric disorders; acute porphyria. Patients receiving voriconazole or rifampicin (weighing ≥50 kg). Discontinue if severe rash or fever develops. Moderate hepatic and severe renal impairment. Childn. Pregnancy.

Patients should be assessed before beginning treatment and during treatment with lamivudine by a physician experienced in the management of chronic hepatitis B.

Severe renal and hepatic impairment. Childn. Pregnancy.

Interaction

Additive CNS effects w/ psychoactive drugs. May alter plasma warfarin concentrations. May reduce plasma concentrations of HIV integrase inhibitors (e.g. dolutegravir), other HIV NNRTIs (e.g. etravirine), HMG-CoA reductase inhibitors (e.g. simvastatin). Plasma concentrations of efavirenz is increased and that of voriconazole is reduced when given concomitantly. Reduced plasma concentrations w/ rifampicin.

Trimethoprim 160 mg / Sulfamethoxazole 800 mg once daily has been shown to increase lamivudine exposure (AUC). The effect of higher doses of trimethoprim /sulfamethoxazole on lamivudine pharmacokinetics has not been investigated.

Decreased plasma concentration with rifampicin resulting in partial or total loss of efficacy of zidovudine. Increased risk of anaemia with ribavirin in patients co-infected with HCV. Antagonistic effect with stavudine or doxorubicn. Increased plasma level with probenecid, atovaquone, valproic acid, fluconazole, or methadone. May alter phenytoin blood levels. Increased adverse effect with potentially nephrotoxic or myelosuppressive drugs (e.g. systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin). Reduced absorption with clarithromycin.

Volume of Distribution

Apparent volume of distribution, IV administration = 1.3 ± 0.4 L/kg. Volume of distribution was independent of dose and did not correlate with body weight.

Apparent volume of distribution, HIV-infected patients, IV administration = 1.6 ± 0.6 L/kg

Elimination Route

Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. The peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL when an oral dose of 2 mg/kg twice a day was given to HIV-1 patients. When given with food, absorption is slower, compared to the fasted state.

Rapid and nearly complete absorption from the gastrointestinal tract following oral administration; however, because of first-pass metabolism, systemic bioavailability of zidovudine capsules and solution is approximately 65% (range, 52 to 75%). Bioavailability in neonates up to 14 days of age is approximately 89%, and it decreases to approximately 61% and 65% in neonates over 14 days of age and children 3 months to 12 years, respectively. Administration with a high-fat meal may decrease the rate and extent of absorption.

Half Life

40-55 hours

5 to 7 hours (healthy or HBV-infected patients)

Elimination half life, HIV-infected patients, IV administration = 1.1 hours (range of 0.5 - 2.9 hours)

Clearance

• Renal clearance = 199.7 ± 56.9 mL/min [300 mg oral dose, healthy subjects]
• Renal clearance = 280.4 ± 75.2 mL/min [single IV dose, HIV-1-infected patients]
• Total clearance = 398.5 ± 69.1 mL/min [HIV-1-infected patients]

• 0.65 +/- 0.29 L/hr/kg [HIV-infected, Birth to 14 Days of Age]
• 1.14 +/- 0.24 L/hr/kg [HIV-infected, 14 Days to 3 Months of Age]
• 1.85 +/- 0.47 L/hr/kg [HIV-infected, 3 Months to 12 Years of Age]. The transporters, ABCB1, ABCC4, ABCC5, and ABCG2 are involved with the clearance of zidovudine.

Elimination Route

Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites.

The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Lamivudine is excreted in human breast milk and into the milk of lactating rats.

As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV.

Pregnancy & Breastfeeding use

Category D: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Lactation: Efavirenz may pass through breast milk and cause serious harm to the baby. It should not be used during lactation.

There is no adequate and well-controlled study in pregnant women. Lamivudine should be used during pregnancy only if the potential benefits outweigh the risks. Although it is not known if lamivudine is excreted in human milk, there is the potential for adverse effects from lamivudine in nursing infants. Mothers should be instructed not to breast feed if they are receiving lamivudine.

Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

Hypersensitivity. Severe hepatic impairment. Lactation. Concomitant admin with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, ergot alkaloids, St John’s wort.

Lamivudine is contraindicated in patients hypersensitive to any of the components of the product.

Hypersensitivity; abnormally low neutrophil counts (<0.75 x 109/L) or Hb levels (<7.5 g/dL or 4.65 mmol/L); newborn infants with hyperbilirubinaemia requiring treatment other than phototherapy, or with increased transaminase levels >5 times the ULN. Lactation. Concomitant use with interferon alfa (with or witho ribavirin) in HIV and hepatitis B or C virus co-infected patients.

Special Warning

Paediatric use: Efavirenz has not been studied in pediatric patients below 3 years of age or who weigh less than 10 kg.

Women taking hormone-based birth control: Women should not rely only on hormone-based birth control, such as pills, injections, or implants, because Efavirenz may make these contraceptives ineffective.

It is recommended that doses of Lamivudine should be adjusted in accordance with renal function. Dosage adjustment of Lamivudine in accordance with creatinine clearance is as follows:

• CrCl 50 ml/min: 100 mg once daily
• CrCl 30-49 ml/min: 100 mg first dose, then 50 mg once daily
• CrCl 15-29 ml/min: 100 mg first dose, then 25 mg once daily
• CrCl 5-14 ml/min: 35 mg first dose, then 15 mg once daily
• CrCl <5 ml/min: 35 mg first dose, then 10 mg once daily

Use in children: Safety and efficacy of lamivudine for the treatment of chronic hepatitis B in children have not been established.

Renal Impairment:

• ESRD maintained on haemodialysis or peritoneal dialysis: 100 mg 6-8 hrly.
• CrCl <10-15 mL/min: 100 mg 6-8 hrly.

Hepatic Impairment: Dose reduction may be needed.

Acute Overdose

Symptoms: Increased adverse CNS effects including involuntary muscle contractions.

Management: Supportive and symptomatic treatment. May administer activated charcoal.

Symptoms: Vomiting, CNS effects (e.g. fatigue, dizziness, drowsiness, lethargy, confusion), haematologic effects (e.g. anaemia, decreased Hb). Bone marrow hypoplasia, mild ataxia, tonic-clonic seizure and increased serum concentration of AST and ALT may also occur. Management: Supportive and symptomatic treatment. Induce emesis and admin activated charcoal to prevent further absorption of unrecovered drug.

Storage Condition

Store at 25°C.

Store below 30˚C. Protect from light. Keep out of the reach of children.

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